Yersinia pestis, the causative agent of plague, is arguably the deadliest pathogen in history, having been credited with at least two-hundred million deaths in modern times. The principal objective of this project is to determine the three-dimensional structures of the Y. pestis effector proteins, a subset of the virulence factors (Yersinia outer proteins, or Yops) that are injected into the cytosol of mammalian cells and enable the pathogen to evade the immune response of the infected organism. We are also interested in specific Yop chaperone (Syc) proteins that are required for the secretion of some effectors. Our long-term goal is to facilitate the design or discovery of effective countermeasures for this potential agent of bioterrorism. In addition, since many important animal pathogens employ a similar virulence strategy (e.g., Shigella spp., enteropathogenic E. coli, Salmonella spp., Pseudomonas aeruginosa, Chlamydia psittaci, and Bordetella spp.), we expect that some of these proteins will be appropriate targets for general "antipathogenicity" drugs. At the same time, we are also trying to identify the targets of Y. pestis effectors in mammalian cells so that we may begin to understand how this infamous bacterium disarms the immune system and multiplies in the lymphoid tissues of its host.